Meloxicam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELOXICAM (meloxicam)

Composition:

Active substance: meloxicam;

1 tablet contains 7.5 mg or 15 mg of meloxicam;

Excipients: lactose monohydrate, maize starch, magnesium stearate, stearic acid, povidone.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets from light yellow to light yellow with a greenish tint.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory drugs (NSAIDs) and antirheumatic agents. ATC code M01A C06.

Pharmacological properties.

Pharmacodynamics.

Meloxicam is a non-steroidal anti-inflammatory drug of the enolic acid class with anti-inflammatory, analgesic and antipyretic effects.

Meloxicam has demonstrated high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its exact mechanism of action remains unknown. However, a common mechanism of action exists for all NSAIDs (including meloxicam): inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics.

Absorption. Meloxicam is well absorbed from the gastrointestinal tract following oral administration, with an absolute bioavailability of 90%. After a single dose of meloxicam, maximum plasma concentration is reached within 5–6 hours for solid oral dosage forms.

Steady-state concentrations are achieved by day 3–5 with repeated dosing. Once-daily dosing results in average plasma concentrations with relatively small peak fluctuations: within 0.4–1.0 µg/mL for the 7.5 mg dose and 0.8–2.0 µg/mL for the 15 mg dose, respectively (Cmin and Cmax at steady state, respectively). The average plasma concentration of meloxicam at steady state is reached within 5–6 hours.

Concomitant food intake or administration of inorganic antacids does not affect drug absorption.

Distribution. Meloxicam is highly bound to plasma proteins, primarily to albumin (99%). Meloxicam penetrates into synovial fluid, where its concentration is approximately half that in plasma. The volume of distribution is low, averaging 11 liters after intramuscular or intravenous administration, with individual variations within 7–20%. The volume of distribution after repeated oral doses of meloxicam (7.5 mg to 15 mg) is 16 liters, with a coefficient of variation ranging from 11% to 32%.

Metabolism. Meloxicam undergoes extensive biotransformation in the liver.

Four different metabolites of meloxicam have been identified in urine, all of which are pharmacodynamically inactive. The main metabolite, 5’-carboxymeloxicam (60% of dose), is formed via oxidation of the intermediate metabolite 5’-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays a major role in the metabolic process, while CYP3A4 isoenzymes contribute to a lesser extent. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. Meloxicam is excreted primarily as metabolites in equal proportions in urine and feces. Less than 5% of the daily dose is excreted unchanged in feces, and a negligible amount is excreted in urine. The elimination half-life ranges from 13 to 25 hours after oral, intramuscular, or intravenous administration. Plasma clearance is approximately 7–12 mL/min after a single oral dose, intravenous or rectal administration.

Dose linearity. Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 mg to 15 mg following oral and intramuscular administration.

Special patient populations.

Patients with hepatic/renal impairment. Mild to moderate hepatic and renal impairment does not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment had significantly higher total clearance. Reduced plasma protein binding was observed in patients with end-stage renal disease. In end-stage renal disease, increased volume of distribution may lead to higher concentrations of free meloxicam. The daily dose should not exceed 7.5 mg (see section "Dosage and administration").

Elderly patients. In elderly male patients, mean pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, AUC values are higher and elimination half-life is longer compared to young volunteers of both sexes. Mean plasma clearance at steady state in elderly patients was slightly lower than in young volunteers.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of osteoarthritis exacerbation.

Long-term symptomatic treatment of rheumatoid arthritis and ankylosing spondylitis.

Contraindications.

• Hypersensitivity to meloxicam or to any of the excipients, or to other active substances with similar action, such as NSAIDs, aspirin. Meloxicam should not be administered to patients who have experienced asthma, nasal polyps, angioedema, or urticaria after taking aspirin or other NSAIDs;
• Third trimester of pregnancy (see section "Use in pregnancy or lactation");
• Pediatric age under 16 years;
• Gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history;
• Active or recurrent peptic ulcer/hemorrhage in medical history (two or more separate confirmed episodes of ulcer or bleeding);
• Severe hepatic impairment;
• Severe renal impairment without dialysis;
• Gastrointestinal bleeding, cerebrovascular bleeding in medical history, or other coagulation disorders;
• Severe heart failure.

Treatment of preoperative pain in coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other forms of interaction.

Studies on interaction were conducted only in adults.

Risks associated with hyperkalemia. Certain medicinal products or therapeutic groups may contribute to hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists, NSAIDs, (low molecular weight or unfractionated) heparins, cyclosporine, tacrolimus, and trimethoprim.

The onset of hyperkalemia may depend on associated factors. The risk of hyperkalemia increases if the above-mentioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions.

Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. Combination with other NSAIDs is not recommended (see section "Special precautions for use"), including acetylsalicylic acid at doses ≥500 mg per single dose or ≥3 g total daily dose.

Corticosteroids (e.g., glucocorticoids). Concomitant use with corticosteroids requires caution due to increased risk of gastrointestinal bleeding or ulceration.

Anticoagulants or heparin. The risk of bleeding is significantly increased due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use"). Concomitant use of NSAIDs and anticoagulants or heparin is not recommended in geriatric practice or at therapeutic doses (see section "Special precautions for use").

In other cases (e.g., prophylactic doses), heparin use requires caution due to increased bleeding risk. Careful monitoring of INR (international normalized ratio) is necessary if this combination cannot be avoided.

Thrombolytic and antiplatelet agents: Increased risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors, and angiotensin II antagonists. NSAIDs may reduce the efficacy of diuretics and other antihypertensive medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors or angiotensin II antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of combination therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive medicinal products (e.g., β-blockers). As with the medicinal products listed below, a reduction in the antihypertensive effect of β-blockers is possible (due to inhibition of vasodilatory prostaglandins).

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus). The nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs due to mediation of effects on renal prostaglandins. Renal function should be monitored during treatment. Careful monitoring of renal function is recommended, especially in elderly patients.

Deferasirox. Concomitant use of meloxicam and deferasirox may increase the risk of gastrointestinal adverse reactions. Caution should be exercised when combining these medicinal products.

Pharmacokinetic interaction: effect of meloxicam on the pharmacokinetics of other medicinal products.

Lithium. Data on NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium) are available, which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section "Special precautions for use"). If combination therapy is necessary, plasma lithium levels should be closely monitored at the beginning of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate. NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high-dose methotrexate (>15 mg/week) (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low-dose methotrexate, particularly those with impaired renal function. If combination therapy is required, blood parameters and renal function should be monitored. Caution is advised when NSAID and methotrexate administration lasts 3 consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase with NSAID treatment (see information provided above) (see section "Adverse reactions").

Pemetrexed. When meloxicam is used concomitantly with pemetrexed in patients with mild to moderate renal impairment (creatinine clearance of 45 to 79 mL/min), meloxicam administration should be suspended 5 days before pemetrexed infusion, on the day of infusion, and for 2 days after infusion. If the combination of meloxicam and pemetrexed is necessary, patients should be closely monitored, particularly for signs of myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance <45 mL/min).

In patients with normal renal function (creatinine clearance ≥80 mL/min), a dose of 15 mg meloxicam may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, caution should be exercised when prescribing 15 mg meloxicam concomitantly with pemetrexed in patients with normal renal function (creatinine clearance ≥80 mL/min).

Pharmacokinetic interaction: effect of other medicinal products on the pharmacokinetics of meloxicam.

Cholestyramine. Cholestyramine accelerates the elimination of meloxicam due to disruption of enterohepatic circulation, resulting in a 50% increase in meloxicam clearance and a reduction in half-life to 13±3 hours. This interaction is clinically significant.

Pharmacokinetic interaction: mutual influence of meloxicam and other medicinal products on pharmacokinetics.

Oral antidiabetic agents (sulfonylureas, nateglinide). Meloxicam is almost entirely metabolized in the liver, two-thirds via cytochrome P450 (CYP) enzymes (mainly CYP 2C9 and secondary pathway CYP 3A4) and one-third via other pathways, such as peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products metabolized by CYP 2C9 and/or CYP 3A4 or those that clearly inhibit these enzymes. Interactions mediated by CYP 2C9 may be expected when meloxicam is used in combination with medicinal products such as oral antidiabetic agents (sulfonylureas, nateglinide); this interaction may lead to increased plasma levels of both agents. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for the development of hypoglycemia.

No clinically significant pharmacokinetic interaction was observed with concomitant administration of antacids, cimetidine, or digoxin.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks provided below).

The recommended maximum daily dose should not be exceeded if the therapeutic effect is insufficient, and additional NSAIDs should not be used, as this may increase toxicity without proven therapeutic benefits. Concomitant use of meloxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Meloxicam is not suitable for treatment of patients requiring relief of acute pain.

If no improvement is observed after several days, the clinical benefits of treatment should be re-evaluated.

Esophagitis, gastritis, and/or peptic ulceration in the patient's history should be carefully considered to ensure complete treatment prior to initiating meloxicam therapy. Patients treated with meloxicam, as well as those with such history, should be regularly monitored for possible recurrence.

Gastrointestinal disorders.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without prior symptoms or serious gastrointestinal disease history.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant low-dose aspirin or other drugs increasing gastrointestinal risks (see information below and section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal toxicity, especially elderly patients, should be informed about any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially during the initial stages of treatment.

Caution should be exercised in patients who are concurrently using drugs that may increase the risk of ulceration or bleeding, including heparin as radical therapy or in geriatric practice, anticoagulants such as warfarin, or other nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid at anti-inflammatory doses (≥500 mg single dose or ≥3 g total daily dose) (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment should be discontinued.

NSAIDs should be used with caution in patients with gastrointestinal disorders in their history (ulcerative colitis, Crohn's disease), as these conditions may worsen (see section "Adverse reactions").

Hepatic disorders.

Elevations in one or more liver function tests may occur in up to 15% of patients receiving NSAIDs (including meloxicam). These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of ALT or AST (approximately 3 times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. Additionally, rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis, and liver failure, some with fatal outcomes, have been reported.

Patients with symptoms or suspicion of hepatic dysfunction or those with abnormal liver function tests should be evaluated for signs of more severe hepatic failure during meloxicam therapy. If clinical signs and symptoms suggest hepatic disease or if systemic manifestations of disease occur (e.g., eosinophilia, rash, etc.), meloxicam use should be discontinued.

Cardiovascular disorders.

Close monitoring is recommended for patients with hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been observed during NSAID therapy.

Patients with risk factors should be clinically monitored for blood pressure at the beginning of therapy, especially at the start of meloxicam treatment.

Data from studies and epidemiological evidence suggest that use of certain NSAIDs (particularly at high doses and during prolonged treatment) may be associated with a small increased risk of vascular thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such risk for meloxicam.

Meloxicam therapy should be initiated only after careful consideration in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similar assessment is required before initiating long-term treatment in patients with cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking).

NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which may be fatal. The risk increases with duration of use. Patients with cardiovascular disease or cardiovascular risk factors may have an increased risk of such complications.

Skin disorders.

Life-threatening severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with meloxicam use. Patients should be informed about signs and symptoms of severe skin reactions and closely monitored for skin reactions. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment. If a patient develops symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis (e.g., progressive skin rash, often with blisters or mucosal involvement), meloxicam treatment should be discontinued. It is important to diagnose promptly and discontinue any drugs that may cause severe skin reactions: Stevens-Johnson syndrome or toxic epidermal necrolysis. This is associated with a better prognosis in severe skin reactions. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis while using meloxicam, the drug must not be re-administered at any time in the future. Fixed drug eruptions have been reported with meloxicam use. Meloxicam should not be re-administered to patients with a history of fixed drug eruption associated with meloxicam. Cross-reactivity with other oxicams is possible.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known sensitivity to meloxicam. The drug should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have a history of rhinitis with or without nasal polyps or who have experienced severe, potentially fatal bronchospasm after aspirin or other NSAIDs. Emergency measures should be taken if an anaphylactoid reaction occurs.

Liver parameters and kidney function.

As with treatment with most NSAIDs, isolated cases of elevated serum transaminases, elevated serum bilirubin or other liver function parameters, as well as increased serum creatinine and blood urea nitrogen, and other laboratory parameter deviations have been described. In most cases, these deviations were minor and transient. If significant or persistent deviations are confirmed, meloxicam use should be discontinued and follow-up tests performed.

Functional renal impairment.

NSAIDs, by inhibiting the vasodilatory effect of renal prostaglandins, may induce functional renal impairment due to decreased glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of diuresis and renal function is recommended at the beginning of treatment or after dose increase in patients with the following risk factors:

• advanced age;
• concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, diuretics (see section "Interaction with other medicinal products and other forms of interaction");
• hypovolemia (of any origin);
• congestive heart failure;
• renal impairment;
• nephrotic syndrome;
• lupus nephropathy;
• severe hepatic dysfunction (serum albumin <25 g/L or ≥10 according to Child-Pugh classification).

In isolated cases, NSAIDs may lead to interstitial nephritis, glomerulonephritis, renal medullary necrosis, or nephrotic syndromes.

The dose of meloxicam in patients with end-stage renal failure on dialysis should not exceed 7.5 mg. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance >25 mL/min).

Sodium, potassium, and water retention.

NSAIDs may enhance sodium, potassium, and water retention and affect the natriuretic effect of diuretics. Additionally, a reduction in the antihypertensive effect of antihypertensive drugs may occur (see section "Interaction with other medicinal products and other forms of interaction"). As a result, edema, heart failure, or hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended for patients with such risks (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia.

Hyperkalemia may be promoted by diabetes mellitus or concomitant use of drugs that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). Regular monitoring of potassium levels is required in such cases.

Combination with pemetrexed.

In patients with mild to moderate renal impairment receiving pemetrexed, meloxicam treatment should be withheld at least 5 days before, on the day of, and for at least 2 days after pemetrexed administration (see section "Interaction with other medicinal products and other forms of interaction").

Other warnings and safety precautions.

Adverse reactions are often less well tolerated in elderly, debilitated, or weakened patients, who require careful monitoring. As with treatment with other NSAIDs, caution is required in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Meloxicam, like any other NSAID, may mask symptoms of infectious diseases.

Meloxicam use may negatively affect fertility and is not recommended for women wishing to become pregnant. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered (see section "Use during pregnancy or breastfeeding").

Meloxicam tablets 7.5 mg and 15 mg contain lactose and therefore should not be taken by patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Masking of inflammation and fever.

The pharmacological action of meloxicam in reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Glucocorticoid therapy.

Meloxicam cannot be a likely substitute for glucocorticoids in the treatment of glucocorticoid insufficiency.

Hematological effects.

Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be related to fluid retention, gastrointestinal bleeding of unknown or macroscopic origin, or incompletely described effects on erythropoiesis. Patients undergoing long-term NSAID treatment, including meloxicam, should have hemoglobin or hematocrit monitored if symptoms and signs of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, short-term, and reversible. Patients taking meloxicam and those with possible adverse effects related to changes in platelet function, including coagulation disorders, or patients receiving anticoagulants, should be carefully monitored.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. Aspirin use in patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, meloxicam should not be used in patients sensitive to aspirin and should be used cautiously in patients with asthma.

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic and fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to about 1.5%. This risk is believed to increase with higher doses and longer duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor led to increased pre- and post-implantation losses and increased embryofetal mortality. Furthermore, in animals receiving a prostaglandin synthesis inhibitor during organogenesis, increased frequency of various developmental abnormalities, including cardiovascular, has been reported.

Starting from the 20th week of pregnancy, meloxicam use may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible after discontinuation of treatment. Additionally, there are reports of arterial duct constriction after treatment in the second trimester, which in most cases resolved after discontinuation of treatment. Meloxicam should not be used during the first and second trimesters of pregnancy, except in cases of extreme necessity. For women attempting to conceive or during the first and second trimesters of pregnancy, meloxicam dosing and treatment duration should be minimal. Prenatal monitoring for oligohydramnios and arterial duct constriction after meloxicam exposure for several days starting from the 20th gestational week may be advisable. The drug should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose risks to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above).

Risks in late pregnancy for mother and newborn:

• prolonged bleeding time, anti-aggregatory effect even at very low doses;
• inhibition of uterine contractions leading to delayed or prolonged labor.

Therefore, meloxicam is contraindicated during the third trimester of pregnancy.

Breastfeeding. Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk. Therefore, use is not recommended for women who are breastfeeding.

Fertility. Meloxicam, like other medicinal products inhibiting cyclooxygenase/prostaglandin synthesis, may negatively affect reproductive function and is not recommended for women wishing to become pregnant. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered.

Ability to influence reaction speed when driving or operating machinery.

No specific studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, based on the pharmacodynamic profile and observed adverse reactions, it can be assumed that meloxicam has no effect or a negligible effect on such activities. Nevertheless, patients experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system disorders, are advised to refrain from driving or operating machinery.

Method of Administration and Dosage

Administer orally.

The total daily dose should be taken once daily with food, swallowed with water or another liquid.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Instructions"). The patient's need for symptomatic relief and response to treatment should be periodically evaluated.

Acute exacerbation of osteoarthritis

Administer 7.5 mg/day (1 tablet of 7.5 mg). If necessary, the dose may be increased to 15 mg/day (1 tablet of 15 mg or 2 tablets of 7.5 mg).

Rheumatoid arthritis, ankylosing spondylitis

Administer 15 mg/day (1 tablet of 15 mg or 2 tablets of 7.5 mg).

See also section "Special Patient Populations" below.

Depending on the therapeutic response, the dose may be reduced to 7.5 mg/day (1 tablet of 7.5 mg).

DO NOT EXCEED THE DOSE OF 15 mg/day.

Special Patient Populations

Elderly patients and patients at increased risk of adverse reactions

The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg daily. Patients at increased risk of adverse reactions should start treatment with 7.5 mg daily (see section "Special Instructions").

Renal impairment

This medicinal product is contraindicated in patients with severe renal impairment who are not on hemodialysis (see section "Contraindications").

For patients with severe renal impairment undergoing dialysis, the dose should not exceed 7.5 mg daily. Dose reduction is not required in patients with mild to moderate renal impairment (i.e., patients with creatinine clearance above 25 mL/min) (for patients with severe renal impairment not undergoing dialysis, see section "Contraindications").

Hepatic impairment

Dose reduction is not required in patients with mild to moderate hepatic impairment (for patients with severe hepatic impairment, see section "Contraindications").

Method of Administration

For oral use.

Meloxicam tablets should be taken with water or another liquid during food intake.

Children Meloxicam tablets (7.5 mg and 15 mg) are contraindicated in children under 16 years of age (see section "Contraindications").

Overdose

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive treatment. Gastrointestinal bleeding may occur. Severe poisoning may lead to hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in cases of overdose.

In case of NSAID overdose, symptomatic and supportive measures are recommended. Studies have shown that meloxicam elimination is accelerated by administration of 4 oral doses of cholestyramine given 3 times daily.

Adverse Reactions

Data from studies and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) may be associated with a small increased risk of vascular thrombotic events (e.g., myocardial infarction or stroke) (see section "Special Warnings and Precautions for Use").

Edema, arterial hypertension, and heart failure have been observed during NSAID therapy.

Most of the adverse effects observed are gastrointestinal in origin. Peptic ulcer, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn's disease have been reported after administration (see section "Special Warnings and Precautions for Use"). Gastritis has been observed less frequently.

Serious skin reactions have been reported, including Stevens–Johnson syndrome and toxic epidermal necrolysis (see section "Special Warnings and Precautions for Use").

The frequency of the adverse reactions listed below was determined based on reported adverse reactions recorded in 27 clinical trials with treatment duration of at least 14 days. The clinical trials involved 15,197 patients who received oral meloxicam in tablet or capsule form at daily doses of 7.5 or 15 mg for up to one year.

Also included are adverse reactions known from post-marketing experience.

Criteria for assessing the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Blood and lymphatic system disorders: uncommon – anemia; rare – blood test abnormalities (including changes in white blood cell count), leukopenia, thrombocytopenia. Very rare cases of agranulocytosis have been reported (see Specific serious and/or common adverse reactions).

Immune system disorders: uncommon – allergic reactions, excluding anaphylactic or anaphylactoid reactions; not known – anaphylactic reaction, anaphylactoid reaction, including shock.

Psychiatric disorders: rare – mood changes, nightmares; not known – confusion, disorientation, insomnia.

Nervous system disorders: common – headache; uncommon – dizziness, somnolence.

Eye disorders: rare – visual disturbances, including blurred vision; conjunctivitis.

Ear and labyrinth disorders: uncommon – dizziness; rare – tinnitus.

Cardiac disorders: rare – palpitations. Heart failure associated with NSAID therapy has been reported.

Vascular disorders: uncommon – increased blood pressure (see section "Special Warnings and Precautions for Use"), flushing.

Respiratory, thoracic and mediastinal disorders: rare – asthma in patients with aspirin or other NSAID allergy; not known – upper respiratory tract infections, cough.

Gastrointestinal disorders: very common – gastrointestinal disorders: dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhea; uncommon – occult or macroscopic gastrointestinal bleeding, stomatitis, gastritis, eructation; rare – colitis, gastroduodenal ulcer, esophagitis; very rare – gastrointestinal perforation; not known – pancreatitis. Gastrointestinal bleeding, ulceration, or perforation may be severe and potentially fatal, especially in elderly patients (see section "Special Warnings and Precautions for Use").

Hepatobiliary disorders: uncommon – liver function test abnormalities (e.g., increased transaminases or bilirubin); very rare – hepatitis; not known – jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: uncommon – angioedema, pruritus, rash; rare – Stevens–Johnson syndrome, toxic epidermal necrolysis, urticaria; very rare – bullous dermatitis, erythema multiforme; not known – photosensitivity reactions, exfoliative dermatitis, fixed drug eruption (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders: uncommon – sodium and water retention, hyperkalemia (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"), changes in renal function parameters (increased serum creatinine and/or urea); very rare – acute renal failure, particularly in patients with risk factors (see section "Special Warnings and Precautions for Use"); not known – urinary tract infections, changes in micturition frequency.

Reproductive system and breast disorders: not known – female infertility, ovulation delay.

General disorders: uncommon – edema, including peripheral edema; not known – influenza-like symptoms.

Musculoskeletal and connective tissue disorders: not known – arthralgia, back pain, joint-related signs and symptoms.

Specific serious adverse reactions. Cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adverse reactions not observed during drug use but generally recognized as characteristic of other compounds in the class. Renal structural injury, which may lead to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children at a temperature not exceeding 25 °C.

Packaging. 10 tablets per blister; 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address.

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine